21-hemi-alpha, beta-dialkylsuccinates of corticoids



i United States Patent Ofiice CH R . wherein R is an alkyl radicalcontaining from one to eight carbon atoms, inclusive; the 1,2 linkage isselected from the group consisting of single bonds and double bonds; Vis selected from the group consisting of hydrogen and methyl; W isselected from the group consisting of hydrogen and fluorine; X isselected from the group consisting of hydrogen, methyl, fluorine andchlorine; E is a generic expression denoting cc and [3 bonds andmixtures thereof; Y is selected from the group consisting of thefi-hydroxymethylene radical fulfill a long recognized need in thepreparation of aqueous solutions from which hydrocortisone and likephysiologically active corticoid hormones can be released into the bloodstream rapidly enough to provide the immediate response necessary inemergency conditions of acute adrenal insuiiiciency, yet also will nothydrolyze on long shelf standing with concomitant precipitation of thefree steroid. Experimental studies conducted under comparable conditionson the hydrolysis of various hemiesters of hydrocortisone and similarcorticoids, showed the u,}8-dialkylhemisuccinates to be the most stableof those tested. The most stable esters of hydrocortisone were found tobe the hemi-a,p-diethylglutarate, hemi-B,B'-dimethylglutarate andhemi-oa,[3-diethy1succinate. The former two hemi-dialkylesters wereshown to be more than five times as stable as the correspondinghemisuccinate, while hydrocortisone 21-hemi-u,p-diethy1- irritation.

3,163,664 Patented Dec. 29, 1964- succinate was found to be between tenand twenty times more stable than hydrocortisone hemisuccinate.

The compounds of this invention are water-soluble, physiologicallyactive derivatives of physiologically active corticoid hormones whichcan be administered parenterally, orally, or topically to humans andvaluable domestic animals without difliculty, and from which thecorticoid hormonal activity is rapidly made available for its intendedfunction.

The compounds of this invention are especially advantageous in thepreparation of ophthalmic solutions, where the precipitation of freesteroids would pose a serious hazard by becoming a potential source ofharmful ocular Ophthalmic solutions of steroidv hemisuccinates on longshelf standing hydrolyze with precipitation of the free steroid,rendering the preparations unsuitable for their intended use. Byemploying steroidal 00,5- dialkylhemiscuccinates instead ofhemisuccinates, the rate of hydrolysis can be greatly slowed to a pointwhere ophthalmic compositions can be prepared that will have a longshelf life.

In carrying out the process of this invention, the free steroidalalcohol is reacted with an excess of the desired carboxylic inneranhydride in a mutual solvent, advantageously, an organic base such aspyridine, lutidine or co'llidine. The reaction take place at temperatureranging from about room temperature to the refluxing temperature of thesolvent employed, with refluxing for from three to six hours beingpreferred. If the anhydride is sufiiciently active or if a longer timeis utilized, temperatures below that of the room can be used.

The product ester can be recovered from the reaction mixture by theusual procedures. Advantageously the product is precipitated by adding aliquid which is capable of precipitating the productas the free acidester or a salt thereof. An aqueous solution of hydrochloric acid orlike strong mineral acid can be used advantageously when pyridine orlike organic base is used as the mutual solvent. Ordinarily it will besuflicient to pour the reaction mixture slowly into an excess of diluteaqueous hydrochloric acid and then filter off the precipitated prodnet.The product can then be further purified by crystallization from asolvent such as acetone. Suitable other solvents include: ethyl acetate,methyl ethyl ketone,

isopropylalcohol and mixtures of the above solvents and Skellysolve B(hexanes) The free acid ester thus produced can be converted to a saltby neutralization with the appropriate base. Advantageously the freeacid ester can be dissolved in a volatile water-miscible solvent, suchas acetone, and the solution neutralized by adding aqueous alkali oralcoholic alkali. Advantageously the pH is adjusted from about 7.2 toabout 7.4. Other volatile water-miscible solvents include: dioxane,isopropyl alcohol, ethanol, and tetrahydrofuran. The solvent is thenremoved by vacuum distillation, first the volatile solvent and then thewater. Advantageously, the water is removed by lyophilizations. Beforelyophilization the Water solution can be filtersterilized if a sterileproduct is desired. Suitable alkalis are the alkali and alkaline earthmetal hydroxides and carbonates, such as sodium, potassium, ammonium,calcium, and magnesium hydroxides and carbonates and lower molecularweight ammonium bases.

oinate) (hydrocortisone ZI-[hydrogen 2,3-die'thylsuc-' cinate] Asolution of 3.64 g. of 11,8,17a,2l-trihydroxy-4-pregnene-3,'2 -dione(hydrocortisone) and 3.64 g. of t p-diethylsuccinic anhydride (preparedin accordance with the method disclosed by Baker in J. Amer. Soc. 65,1577 [1943] or Steinkopf et al. in Annalen 546, 199 [1941]) in 36 ml. ofdry pyridine was refluxed for a period of about 4 hours, cooled andadded with stirring to a mixture of 550 g. of ice and 55 ml. ofconcentrated hydrochloric acid. The mixture was extracted with three 120ml. portions of methylene chloride and the combined organic layerswashed first with 100 m1. of dilute (ca. 2%) hydrochloric acid and thenwith water. The organic layer was extracted with four 120 ml. portionsof saturated sodium bicarbonate solution, which was then acidifiedcarefully with 90 ml. of 1:1 concentrated hydrochloric acid-water. Theacidified aqueous layer was extracted with three 120 ml. portions ofethyl acetate. The combined ethyl acetate layers were washed withsaturated sodium chloride solution, dried over anhydrous sodium sulfate,filtered and concentrated to dryness under reduced pressure. The residuewas slurried with anhydrous ether, filtered and dried, to yield 2.17 g.of product with a melting point of 159.5 to 163 C. This solid wasdissolved in 15 ml. of acetone, clarified by filtration and the solutionconcentrated on a steam bath -to about 10 ml. Crystallization occurredupon the addition of 3 to 4 ml. of Skellysolve B (hexanes) to yield 820mg. of 1lfi,17a,21-trihydroxy-4- pregnene-3,2 -dione21-hemi-a,fi-diethylsuccinate with a melting point of 168.5 to 171 C. Asample prepared subsequently meltedat 206 to 208.5 C.

AI1alysiS.Calcd. fOl' 02913420 C, H, 8.16. Found: C, 66.96; H, 8.34.

The infrared and ultraviolet spectra of the thus prepared compoundsupport its proposed structure.

Example 2 17 01,2l-dihydroxy-4-pregnene 3,11,20-trione21-hemi-a,fl-diethylsuccinate (cortisone21-116I1'1i-0gfi-di6thyls'uccinate) Following the procedure of Example1, but substituting cortisone for hydrocortisone as starting material,yields cortisone 21-hemi-a,}3-diethy1succinate.

Example 3 l1fi,17a,21-trihydroxy-1,4 pregnadiene 3,20 dione 21-hemi-mfi-diethylsuccinate (l-dehydrohydrocortisone 21-hemi-a,,B-diethylsuccinate) Following the procedure of Example 1, butsubstituting l-dehydrohydrocortisone for hydrocortisone as startingmaterial, yields 11p,17u,2l-trihydroxy-1,4-pregnadiene 3,20-d-ione21-hemi-a,)8-diethylsuccinate.

Example 4 6a-methyl-11/3,17a,2l-trihydroxy-1,4-pregnadiene 3,20- dione2l-hemi-a, 8-diethylsuccinate (6u-rnethyl-1-dehydrohydrocortisone2l-hemi-a,fl-diethylsuccinate) Following the procedure of Example 1, butsubstituting 6a-methyl-1-dehydrohydrocortisone for hydrocor-tisone asstarting material, yields 6a-methyl-11B,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione 21 hemi-a,B-diethylsuccinate with a meltingpoint of 185 to 194 C.

Example (a) 6afluoro-1 1B, 17,21-trihydroxy-4-pregnene-3,20-

dione 21-hemi-a,;8-diethylsuccinate;

(b) 6,3-fiuoro-1118,1711,21-trihydroxy-4-pregnene-3,20-

dione 21-hemi-a,e-diethylsuccinate;

(c) 6a-fiuoro-11,8,17a,21-trihydroxy-1,4-pregnadiene- 3,20-dione21-hemi=a,fl-diethylsuccinate;

(d) 6B-fiuoro-l 119,17a,2l-trihydroxy-1,4-pregnadiene- 3,20-dione21-i1emi-a, fi-diethylsuccinate;

(e) 6a-ohloro-l119,17a,21-trihydroxy-4-pregnene-3,20- dione 21hemi-a,B-diethylsuccinate; v (f)6/3-chloro-11,8,170:,21-trihydroxy-4-pregnene-3,20-

dione 2l-hemi-mfi diethylsuccinate;

4 (g) 6a-chloro-1 1fl,17a,21-trihydroxy-1,4-pregnadiene- 3,20-dione21-hemi-u,fl-diethylsuccinate; (h)6fl-chloro-11B,17a,21-trirhydroxy-1,4-pregnadiene- 3,20-dione21-hemi-a,B-diethylsuccinate.

Carrying out the procedure of Example 1, but substituting forhydrocortisone, the following starting materials:

6afil10r0-1 1,8, 17(1,21-trihydroxy-4-pregnene-3 ,ZO-dione,

Gfl-fiuoro-l 113,17a,21-trihydroxy-4-pregnene-3,20-d1one,

6a-flllOI'O-1 1p,17a,21-trihydroxy-l,4-pregnadiene-3,20-

dione,

6,8-fluoro-1 1B,17a,2l trihydroxy-1,4-pregnadiene-2,20-

dione,

6a-Ch10r0-1 13,17;1-trihydroxy-4-pregnene-3,ZO-dione,

Sfi-chloro-l 1,8,17a, 21-trihydroxy-4-pregnene:3,20-drone,

6a-chloro-1 1,8,17a,21-trihydroxy-1,4-pregnad1ene-3,20-

dione and 6fi-chloro-1,3,170:,21-trihydrcxy-1,4-pregnadrene-3,20*

dione,

yields, respectively, the corresponding 2l-hemi-a,p8-diethylsuccinatesthereof, set forth in (a) to (h), inclusive, above.

Example 6 11,8,17a,21-trihydroxy-4-pregnene-3,20 dione 21hemia,/8-dimethylsuccinate (hydrocortisone ZI-hemi-dimeth ylsuccinate) Asolution of 3.6 g. of 11fi,17a,2l-trihydroxy-4-preg= nene-3,20-dione(hydrocortisone) and 3.5 g. of a,fl-di' methylsuccinic anhydride(prepared in accordance with the method disclosed fora,fl-diethylsuccinic anhydride in J. Amer. Chem. Soc. 65, 1957 [1943]except that ac= etaldehyde cyanohydrin and methyl bromide are sub=stituted for propionaldehyde cyanohydrin and ethyl iodide) in 36 ml. ofdry pyridine is refluxed for a period of about 4 hours, cooled and addedwith stirring to a mixture of 550 ml. of ice and 55 ml. of concentratedhydrochloric acid. The mixture is extracted with three 120 m1. portionsof methylene chloride and the combined organic layers washed first withml. of dilute (ca. 2%) hydrochloric acid and then with water. Theorganic layer is extracted with four ml. portions of saturated sodiumbicarbonate solution, which is then acidified carefully with 90 ml. of1:1 concentrated hydrochloric acid=water. The acidified aqueous layer isextracted with three 120 ml.- portions of ethyl acetate. The combinedethyl acetate layers are washed with saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to drynessunder reduced pressure. The residue is slurried with anhydrous ether,filtered and dried, to yield the desired product. Dissolving thisproduct in acetone and filtering, followed by the addition of a smallvolume of Skellysolve B to the filtrate yields crystalline11fl,17a,2ltrihydroxy-4-pregnene-3,ZO-dione 21hemi-a,B-dimethyls'uccinate.

Carrying out the procedure of Example 6, but substituting fora,fl-dimethylsuccinic anhydride, the following anhydrides (normal andiso):

a,,B-dipropylsuccinic, u,fi-dibutylsuccinic, a,B-dipentyl, a,5-dihexyl,a,/3-diheptyl and a,/3-dioctyl,

yield, respectively, the corresponding11fi,17a,21-trihydroxy-4-pregnene-2,30-dione 2l-hemi-a,6dialkylsuccinates.

Example 7 (a) 17a,2 l-dihydroxy-4-pregnene-3,1 1,20-trione2l-hemia,p-dimethylsuccinate;

(b) 11,8,17a,21-trihydroxy-1,4-pregnadiene-3,20-dione 2.l-

V hemi-a, 8-dimethylsuccinate;

() 6u-methyl-11B,17u,21-trihydroxy-4-pregnene 3,20

dione 21-hemi-a,/3-dimethylsuccinate;

(d) Ga-methyl-l1,6,17a,21-trihydroxy- 1,4 pregnadiene- 3,20-dione21-hemi-u,;8-dimethylsuccinate;

(e) 6a-fluoro-11,8,176:,21-trihydroxy-4-pregnene-3,20 dione21-herni-a,;3-dimethylsuccinate;

(f) 6B-fluoro-l1B,170;,21-trihydroxy-4-pregnene-3,20 di- I one21-hemi-a,;3-'dimethylsuccinate;

(g) 6a-fluoro-1v1fi,l7a,-21-trihydroxy 1,4 pregnadiene- 3,20-dione21-hemi-a,B-dimethylsuccinate;

(h) 6 8-fluoro-11 3,17u,21-trihydroxy 1,4 pregnadiene- 3,20-dione21-hemi-a, 8-dimethy1succinate;

(i) 6u-chl0ro-11,8,17u,21-trihydroxy 4-pregnene-3,20 dione21-hemi-a,/8-dimethylsuccinate;

(j) 6 3-chloro-l1B,l7u,21-trihydroxy-4-pregnene-3,20 dione21-herni-a,B-dimethylsuccinate;

(k) 6a-chloro-11/3,17a,21-trihydroxy-1,4 pregnadiene:

3,20-dione 21-hemi-a,,8-dimethy1succinate;

(l) 6,8-chloro-11B,l7u,21-trihydr0xy 1,4 pregnadiene- 3,20-di'one21-hemi-a,;3-dimethylsuccinate.

Carrying out the procedure of Example 6, but substituting forhydrocortisone, the following starting materials:

17 a,2 l-dihydroxy-4-pregnene-3,1 1,20-trione, 1 1,8,170:,21-t1ihYd1'0XY- 1 ,4-pregnadiene-3,20-dione, 6a-rnethyl-1113,17u,21-trihydroxy-4-pregnene-3,ZO-dione,6a-methyl-l1B,17u,21-trihydroxy-1,4-pregnadiene 3,20-

dione, Goa-fllIOIO-l 118,17a,21-trihydroxy-4-pregnene-3 ,20 dione,6B-fluoro- 1 1B, 1761,21-trihydroxy-4-pregnene-3 ,20-dione,6afluoro-11p,17a,21-trihydroxy-1,4 pregnadiene 3,20-

dione, 6,8-fluoro-11,9,17u,21-trihydroxy-l,4

dione, I 6oc-Chl0IO-1 1,8,176:,21-trihydroXy-4-pregnene-3 ,ZO-dione,6p-chloro-11,3,17a,21-trihydroxy-4-pregnene-3,20 dione, 6 x-Chl01011p,175,2l-trihydroxy-1,4-pregnadiene 3,20- dione and pregnadiene 3,20-

6fl-chloro-1 1,8,17a,2l-trihydroxy-1,4-pregnadiene V 3,20-

dione,

yield, respectively, the corresponding 21-hemi-a,fl-dimethylsuccinatesthereof, set forth in (a) to (l), inclusive, above.

Carrying out the procedure of Example 6, but substituting fora,}8-dimethylsuccinic anhydride, the following anhydrides (normal andiso):

a,,8-dipropylsuccinic, u,;8-dibutylsuccinic, a,fl-dipentylsuccinic,a,/3-dihexylsuccinic, a,,B-diheptylsuccinic and a,,8-dioctylsuccinic,yield, respectively, the corresponding 21-hemi-a,{3-dialkylsuccinates ofthe starting materials disclosed in the inn mediately precedingparagraph.

Exwmple 8 (a) 17a,2ll-dihydroxy-1,4-pregnadiene-3,11-20-trione 21-hemi-a,fi-diethylsuccinate; (b)6u-rnethyl-1lfi,l7a,21-trihydroxy-4-pregnene-3,20 -dione 21-hemi-a,3-diethy1succinate;

(c) 2a-rnethyl-9a-fluoro-11B,17a,21-trihydroxy-4 pregnene-3,20-dione21-hemi-a, 3-diethylsuccinate;

(d) 9u-fluoro-11B,17u,21-trihydroxy-1,4' pregnadiene- 3,20-dione21-herni-a,/3-diethylsuccinate;

(e) 16a-fluoro-11 3,17a,21-trihydroxy-1,4 pregnadiene- 3,20-dione21-he1ni-u,,8-diethylsuccinate;

(f) 9a,l6a-difluoro-l1fi,17a,21-trihydroxy-1,4 pregnadiene-3,20-dione21-hemi-a, 3-diethylsuccinate.

Carrying out the procedure of Example 1, but substituting forhydrocortisone, the following starting materials:

a,/3-dimethylsuccinic, a,fi-dipropylsuccinic,

V afi-dibutylsuccinic,

yield, respectively, the corresponding 21-hemi-a,/3-dialkylsuccinates ofthe starting materials disclosed in the immediately preceding paragraph.

We claim:

1. 11 3,17 ,21-trihydroxy-4-pregnene-3,20 dione 21-hemi-a,5-dialkylsuccinate.

2. 11,8,17oc,21-trihydroxy-4-pregnene-3,20'- dione 21-hemi-a,,8-diethylsuccinate.

3. 11B,17a,2Ltrihydroxy-1,4-pregnadiene-3,20-dione 21-hemi-a,/3-dialkylsuccinate.

References Cited by the Examiner UNITED STATES PATENTS 10/53 Minlon260397.4 6/58 Spero 260397.45 6/58, Spero 260-23955 1/59 Johnson 167773/59 Johnson l6765 6/59 Hanze 260397.45 4/60 Ringold et al. 260-397.47

OTHER REFERENCES Ringold et al.: Journal of American Chemical Soc.,(1958) vol. page 6464.

7 LEWIS GOTTS, Primary Examiner.

1. 11B,17A,21-TRIHYDROXY-4-PREGNENE-3,20- DIONE21HEMI-A,B-DIALKYLSUCCINATE.